BERKELEY, CA (UroToday.com) - Despite many advances in technology and medicine, the treatment of high-grade, high-risk prostate cancer continues to be prone to recurrence. The standard of care for patients who are either not candidates for surgery, or who elect not to pursue surgery is combination androgen suppression therapy with external beam radiation therapy using intensity modulation (IMRT). Unfortunately, even with this approach, treatment failures are still seen in a substantial proportion of patients, particularly over longer time intervals (i.e., > 10 years). In this setting, adenoviral gene therapy offers a safe and attractive platform to augment such traditional therapies, particularly since these vectors have been demonstrated to have synergy of effect with high dose rate radiation. However, these prostate specific vectors require the presence of androgens to achieve maximal activity, making them unsuitable for patients on active androgen suppressive therapy. As a result, translation of this combination therapy for high-risk patients (Gleason 7 or higher, T2 or higher) has been hampered. In order to overcome this limitation we have recently generated and published a novel adenoviral construction which is capable of being activated by either androgens or non-steroidal antiandrogens (bicalutamide).[1] This is achieved by fusing the adenoviral E1A gene to a mutated androgen receptor gene with a point mutation in the ligand binding domain which confers activation by either androgens or anti-androgens.[2] Studying the biology of this point mutation we found that the mutated E1A-AR (C685Y) fusion retained ability to function both in regulating AR responsive genes and the viral genes. The construct is extremely specific, being activated only in prostate cells which are irradiated, and only in the presence of either androgen or non-steroidal anti-androgens such as bicalutamide.
This novel diseased-based vector design will help to augment the ability of radiation therapy to treat patients with clinically localized high-risk disease who typically present with Gleason 7 or higher disease and with T2 or higher lesions. Even when clinically organ confined, these patients have an unusually high relapse rate, and once this occurs, many patients progress and die of disease. There are fundamentally two different reasons why it is thought such patients fail therapy: (1) high grade disease develops resistance to radiation therapy, even when given with hormone therapy in IMRT protocols, and (2) high-risk patients frequently have micro-metastatic disease at presentation, which is not detectable by our current conventional imaging technologies. Our approach seeks to address both these concerns. Namely, patients with radiation resistant disease will have their cancers sensitized to therapy by the adjuvant use of a highly engineered adenovirus vector, designed to be combined with non-steroidal anti-androgen therapy which is activated by radiation in a synergistic fashion. Similarly, virus injected directly into the prostate will egress from the prostate through the the same channels available to the tumor cells (hematogenous and lymphatic) and potentially infect and replicate selectively in those cells which are susceptible. If anti-tumor immunity is induced, even systemic disease may respond favorably to the approach. The impact of this approach could be profound, as it would augment current conventional standard of care therapy with minimal impact on morbidity and with minimal modification of current IMRT protocols.
References:
- Johnson TJ, Höti N, Liu C, Chowdhury WH, Li Y, Zhang Y, DeWeese TL, Rodriguez R. Bicalutamideactivated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer.Cancer Gene Therapy 2013 20, 394 402
- Ceraline J, Erdmann E, Erbs P, Deslandres-Cruchant M, Jacqmin D, Duclos B et al. A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer. Eur J Endocrinol 2003; 148: 99–110.
Written by:
Naseruddin Höti, MPhil, PhD, DSca and Ronald Rodriguez, MD, PhDb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
a Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD. USA
bDepartment of Urology, UT Health Science San Antonio, TX. USA
Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer - Abstract
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